- Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
-
Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5-and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′-and 5′-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor.
- Cheng, Xinlai,Merz, Karl-Heinz,Vatter, Sandra,Zeller, Jochen,Muehlbeyer, Stephan,Thommet, Andrea,Christ, Jochen,W?lfl, Stefan,Eisenbrand, Gerhard
-
supporting information
p. 4949 - 4962
(2017/06/28)
-
- IMPROVED CATIONIC LIPIDS AND METHODS FOR THE DELIVERY OF THERAPEUTIC AGENTS
-
The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel cationic lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of a specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
- -
-
Page/Page column 154
(2011/02/24)
-
- COMPOSITIONS AND METHODS FOR SILENCING APOLIPOPROTEIN B
-
The present invention provides compositions and methods for the delivery of interfering RNAs that silence APOB expression to liver cells. In particular, the nucleic acid-lipid particles provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of APOB at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
- -
-
-
- COMPOSITIONS AND METHODS FOR SILENCING EBOLA VIRUS GENE EXPRESSION
-
The present invention provides compositions comprising therapeutic nucleic acids (e.g., interfering RNA such as siRNA) that target Ebola virus (EBOV) gene expression and methods of using such compositions to silence EBOV gene expression. More particularly, the invention provides unmodified and chemically modified interfering RNA which silence EBOV gene expression and methods of use thereof, e.g., for preventing or treating EBOV infections caused by one or more EBOV species such as Zaire EBOV. The invention also provides serum-stable nucleic acid-lipid particles comprising one or more interfering RNA molecules, a cationic lipid, and a non-cationic lipid, which can further comprise a conjugated lipid that inhibits aggregation of particles. Methods of silencing EBOV gene expression by administering one or more interfering RNA molecules to a mammalian subject are also provided.
- -
-
-
- rac-3,4-DIHYDROXYBUTYLARSONIC ACID: A KEY INTERMEDIATE FOR ISOSTERIC ARSONOLIPIDS
-
Synthetic routes starting from 4-bromobut-1-ene and leading to rac-dihydroxybutylarsonic acid and diphenyl rac-3,4-dihydroxybutyldithioarsonite were explored.All of them gave overall yields 5-16percent.Some properties of the free acid and its dilithium salt are described. Key words: Arsonic acids, (diethylamino)chlorarsine, the Mayer reaction,salts of arsonic acids, cyclization of arsonic acids.
- Serves, Spyros V.,Sotiropoulos, Demetrios N.,Ioannou, Panayiotis V.,Mutenda, Esther K.,Sparkes, Michael J.,Dixon, Henry B.F.
-
-
- Enzymes in Organic Synthesis, 11. Expedient Enantioselective Synthesis of (S)-(-)-3,4-Dihydroxybutylphosphonate, an Isosteric Substrate Mimic for Glycerol Phosphate Oxidase
-
The title compound (S)-(-)-2 was obtained in enantiomerically pure form and 47percent overall yield starting from (S)-malic acid (S)-7 by a 5-step sequence involving reduction to (S)-1,2,4-butanetriol (S)-8, acetalization, and introduction of the phosphonate group by an Arbusow reaction.Compound (S)-(-)-2 is a substrate for the L-glycerol 3-phosphate oxidase from Pediococcus sp. which quantitatively converts it into 4-hydroxy-3-oxobutylphosphonate 4, an isosteric analog of dihydroxyacetone phosphate.Kinetic constants of the latter reaction were determined. - Keywords: Dihydroxyacetone phosphate mimic; Enzymatic synthesis; Glycerol phosphate oxidase; Sugar phosphonates
- Arth, Hans-Lothar,Sinerius, Gudrun,Fessner, Wolf-Dieter
-
p. 2037 - 2042
(2007/10/03)
-